. The overall objective of this renewal is to determine the genetic etiology and clinical characteristics of high risk familial colon cancer. High risk familial colon cancer accounts for 10 to 20% of colon cancer cases. It is defined when there are two first degree relatives with colon cancer or a single case diagnosed at an age <50 years. Family members in this situation are at three- to six-fold increased risk for colon cancer and special screening has been recommended. Some fraction of these high risk cases arise from hereditary non-polyposis colorectal cancer (HNPCC), familial adenomatous polyposis (FAP) or attenuated adenomatous polyposis coli (AAPC), but most do not. The fraction of high risk cases that arise from FAP, AAPC and HNPCC will first be determined by identifying all high risk cases in the Utah Population Data Base, a data base that combines Utah cancer and genealogy resources. Records and archival tissues will be used to find which of these high risk individuals has FAP (records) and which has HNPCC or AAPC (genetic diagnosis). High risk cases that do not have one of these syndromes will then serve as index cases to select a number of suitable kindreds for further study. Kindreds will be expanded and kindred members will undergo colonoscopy to define the polyp and cancer phenotype. Linkage analysis will then be done to identify new polyp and cancer susceptibility loci. A precise clinical and genetic definition of this high risk familial category is needed so that affected families can be accurately identified, screened and managed, and so that genetic screening and testing for the rare syndromes and for additional susceptibility loci can be applied widely in this group.